β-cell-specific Non-invasive Ultrasound Stimulation to Enhance Insulin Release and Glucose Control in Mice

Diabetes poses a significant global health burden, with complications such as cardiovascular disease, stroke, and kidney failure. While insulin therapy is central to type 2 diabetes (T2D) management, its limitations—including rapid degradation and the need for frequent injections—highlight the demand for non-invasive alternatives. Here, we present an ultrasound (US)-mediated approach to enhance insulin release by selectively stimulating pancreatic β-cells via targeted microbubbles (MBs). In vitro experiments using RINm5F β-cells demonstrated that US-MB stimulation induces significant calcium influx and subsequent insulin release. In addition, this method effectively decreased blood glucose levels in mice by promoting insulin release. Mechanistic studies revealed that mechanosensitive ion channels play a pivotal role, as their inhibition (via GdCl ₃ ) abolished the ultrasonic effect. Importantly, the approach exhibited high biosafety, with no detectable cell death or tissue damage. Our findings establish ultrasound-stimulated β-cell targeting as a promising non-invasive strategy for diabetes treatment, offering a potential alternative to conventional insulin therapy.